Abstract Our long-term goal is to understand the detailed molecular mechanisms and cellular events that control palate development (palatogenesis). Failure in palatogenesis results in cleft palate, which is one of the most common birth defects in humans. During the final phases of palatogenesis, the palatal periderm (PD, a protective outer cell layer that prevents premature adhesion) must be removed in order for the medial edge epithelia (MEE) to properly adhere, which is prerequisite for appropriate palatogenesis. The previous studies have shown that transforming growth factor-?3 (TGF?3), plays an irreplaceable role in palate development, both in mice and humans, by regulating the fate of the MEE and adjacent periderm in fusing palatal shelves. Our recent data were the first to suggest that Tgfb3 is necessary for periderm degeneration. However, deeper understanding of the role of periderm-specific signaling events during palate adherence and fusion has been hampered by the fact that until now, there have been no satisfactory periderm-specific Cre-driver lines available for the scientific community. In addition, the previous studies employing a commonly used K14Cre driver line to examine the epithelium-specific signaling in palatogenesis have ignored the fact that K14Cre does not recombine in the periderm, and thus these studies have failed to reveal relevant cell type-specific details of this important signaling mechanism. Due to these impediments, several pertinent questions have remained unanswered. Our present preliminary data demonstrate that the cytokeratin-6a (K6a) locus can effectively be used to generate specific and robust periderm-specific Cre driver lines. We hypothesize that the periderm-specific K6a- based Cre drivers allow us to define the PD-fate and establish the PD-specific cell-autonomous role for TGF-? signaling in induction of adherence between apposing palatal shelves during palatogenesis. The details of these mechanisms will be determined through execution of two specific aims. In Aim 1, we propose to determine the fate of periderm cells during palatogenesis using a novel inducible periderm-specific Cre line; and in Aim 2, we propose to determine the cell-autonomous role of TGF-? signaling in the palatal periderm during palatal epithelial fusion. Successful completion of the proposed experiments will provide improved PD-specific tools for the scientific community and define the cell-autonomous role of TGF-? signaling in the PD; this knowledge may contribute in development of more advanced therapeutic strategies in the future.